The recently identified sigma receptor/binding site of the brain is an important target for the development of antipsychotic drugs that are free from the side affects of currently available antipsychotic drugs having antagonistic activity on the dopamine D2 receptor (J. M. Walker and W. D. Bowen, F. O. Walker and R. R. Matsumoto, B. de Costa and K. C. Rice, Pharmacological Reviews, 42, pp. 355–402, 1990; G. Debonnel, J. Psychiatr. Neurosci., 18, 4, pp. 157–172, 1993; G.Debonnel and C. de Montigny, Life Sciences, 58, 9, pp. 721–734, 1996). Further, some data have been reported that suggest the regulation of signal transmission by a sigma ligand (also referred to as “sigma receptor ligand” in the specification) and its receptor through control of a calcium level in synaptosomes (P. J. Brent, H. Saunders and P. R. Dunkley, Neurosci. Lett., 211, pp. 138–142, 1996).
The term “receptor” used herein means a membrane binding type receptor and other binding sites. Existence of at least two sorts of sigma receptor subtypes, i.e., sigma 1 and sigma 2, has been revealed, and classification of sigma binding sites has been proposed (R. Quirion, W. D. Bowen, Y. Itzhak, J. L. Junien, J. M. Musacchio, R. B. Rothman, T. P. Su, W. Tam and D. P. Taylor, TiPS, 13, pp. 85–86, 1992). The sigma 1 binding site is characterized to have high affinity for haloperidol, di-o-tolylguanidine (DTG) and (+)-benzomorphane such as (+)-pentazocine, whilst the sigma 2 binding site is characterized to have high affinity for haloperidol and DTG, but have low affinity for (+)-benzomorphane.
The sigma 1 ligand has an action on the gastrointestinal tract, and it seems that the sigma 1 site may mediate suppression to muscarine-like acetylcholine receptor/phosphoinositide response by the sigma ligands. The sigma 1 binding site is present not only in brains, but on spleen cells (Y. Lin, B. B. Whitlock, J. A. Pultz and S. A. Wolfe Jr, J. Neuroimmunol., 58, pp. 143–154, 1995), and such sigma ligands may suppress the immune system (H. H. Garza, S. Mayo, W. D. Bowen, B. R. DeCosta and D. J. J. Carr, J. of Immunology, 151, 9, pp. 4672–4680, 1993).
The sigma 2 binding site is abundant in livers (A. E. Bruce, S. B. Hellewell and W. D. Bowen, Neurosci. Abstr., 16, 370, 1990; A. S. Basile, I. A. Paul and B. DeCosta, Eur. J. Pharmacol. Mol. Pharm. Sect., 227, pp. 95–98, 1992; C. Torrence-Campbell and W. D. Bowen, Eur. J. Pharmacol., 304, pp. 201–210, 1996), kidneys (W. D. Bowen, G. Feinstein and J. S. Orringer, Soc. Neurosci. Abstr., 18, 456, abstract 195.8, 1992), and hearts (M. Dumont and S. Lemaire, Eur. J. Pharmacol., 209, pp. 245–248, 1991).
The sigma 2 binding site in brains exists in hypothalamus, cerebellum, pons medulla and medulla oblongata. In hippocampus, frontal lobe and occipital lobe in rat brains, it exists more abundantly than the sigma 1 binding site (D. J. McCann, A. D. Weissmann and T. P. Su, Soc. Neurosci. abstr. 18, 22, abstract 16.5, 1992). In hippocampus synaptosomes of guinea pig, there are also the sigma 2 binding site that is selectively labeled with [3H] BIMU (D. W. Bonhaus, D. N. Loury, L. B. Jakeman, Z. To, A. DeSouza, R. M. Eglen and E. H. F. Wong J. Pharmacol. Exp. Ther., 267, 2, pp. 961–970, 1993). The relationship between the sigma 2 binding site and cortex as well as limbic system supports the usefulness of compounds used for treatment of mental diseases (D. C. Mash and C. P. Zabetian, Synapse, 12, pp. 195–205, 1992).
It has been believed that the sigma 2 binding site is involved in motility functions, especially dystonia (R. R. Matsumoto, M. K. Hemstreet, N. L. Lai and A. Thurkauf, B. R. DeCosta, K. C. Rice, S. B. Hellewell, W. D. Bowen and J. M. Walker, Pharmacol. Biochem. Behav., 36, pp. 151–155, 1990). However, no evidence demonstrating such an action has been found in primate models of functional disorders of extrapyramidal tract (L. T. Meltzer, C. L. Christoffersen, K. A. Serpa, T. A. Pugsley, A. Razmpour and T. G. Heffner, Neuropharmacology, 31, 9, pp. 961–967, 1992).
Haloperidol, which is a clinically effective dopaminergic antipsychotic agent, shows high affinity for these two sigma subtypes. However, a reduced metabolite of haloperidol that acts on the central nervous system has more excellent affinity and selectivity for the sigma 2 receptor than dopamine D2 as compared to haloperidol (J. C. Jaen., B. W. Caprathe, T. A. Pugsley, L. D. Wise and H. Akunne, J. Med. Chem., 36, pp. 3929–3936, 1993). Since a selective agent has not been available, pharmacological significance, distribution and functions of the sigma 2 binding site have not yet been elucidated. On the other hand, recent studies revealed that the sigma 2 site played a role for controlling functions of ileum (G. G. Kinney, E. W. Haris, R. Ray and T. J. Hudzik, Europ. J. Pharmacol., 294, pp. 547–553, 1995). These data suggest that the selective sigma 2 ligand is useful for the treatment of irritable bowel syndrome.
Such sigma ligands are disclosed in Japanese Patent Application Laid-Open No. 9-302607, Japanese National Phase PCT Laid-Open Publication No. 10-508826 and the like. However, no cyclic amide derivative, such as isoindoline-1-on as a typical example, has been described yet.
As compounds which have a similar structure to those of general formula (I) of the present invention, Japanese National Phase PCT Laid-Open Publication No. 7-506107 discloses 4-imidomethyl-1-[2′-phenyl-2′-oxoethyl]piperidines such as:
and hydrochlorides thereof and the like. However, these compounds are described as serotonine 2 antagonists, and whether or not they can act as sigma ligands has not yet been known. Moreover, these compounds having a phthalimide group may probably have a problem of insufficient safety.